Assessment of As Needed Use of Pharmacotherapy and the Pause-Squeeze Technique in Premature Ejaculation

Assessment of as needed use of pharmacotherapy and the pause-squeeze technique in premature ejaculation

IA Abdel-Hamid1*, EA El Naggar2 and A-H El Gilany3

1Department of Andrology, Mansoura Faculty of Medicine, Mansoura, Egypt; 2Department of Psychiatry, Mansoura Faculty of Medicine, Mansoura, Egypt; and 3Department of Community Medicine, Mansoura Faculty of Medicine, Mansoura, Egypt

The objective was to compare the ef®cacy and safety of the as needed use of clomipramine, sertraline, paroxetine, sildena®l and the pause-squeeze technique in treatment of primary premature ejaculation. A prospective double blind randomized crossover study involving 31 patients was performed. Treatment phases comprised ®ve 4-week consecutive treatment periods, each separated by a two-week washout period. Patients were randomly assigned to receive each of the 4 drugs and use pause-squeeze on an as needed basis. Drugs were administered 3 to 5 hours before anticipated coitus. Anxiety score and ejaculation latency time were measured before treatment, after each treatment, and during washout periods. Sexual satisfaction score was measured after each treatment. The median ejaculation latency time was signi®cantly increased from the pretreatment median of 1 minute to 4 minutes, 3 minutes, 4 minutes, 15 minutes and 3 minutes during treatment with clomipramine, sertraline, paroxetine, sildena®l and pause-squeeze technique, respectively (all P 0.0001). Sildena®l was superior to other modalities in terms of ejaculation latency and satisfaction (P 0.0001). The three antidepressants were comparable to each other in terms of ef®cacy (P > 0.05). Paroxetine was superior to the pause-squeeze technique in terms of ef®cacy (P < 0.05). In conclusion, sildena®l appears to be superior to other modalities and a valid alternative in treatment of premature ejaculation. The 3 antidepressants were equivalent to each other in terms of ef®cacy and safety. Paroxetine was superior to pause-squeeze technique in terms of ef®cacy. International Journal of Impotence Research (2001) 13, 41±45.

Keywords: premature ejaculation; behavioral therapy; antidepressants; sildena®l

Introduction documented the success of this modality when used as needed in the treatment of premature ejaculation.2,10 Recent knowledge has been gained with Premature ejaculation has been treated with various oral sildena®l treatment of psychogenic impotence. modalities. These modalities include behavioral Sildena®l is a potent and selective inhibitor of cyclic therapy,1,2 topical applications,3 oral pharmacother- guanosine monophosphate (cGMP)-speci®c phos- apy,4±6 and intracavernosal vasoactive drug injec- phodiesterase type 5. It thus enhances the relaxant tion.7 Oral pharmacotherapy such as the tricyclic effect of nitric oxide released in response to sexual antidepressant, clomipramine, and serotonin re- stimulation by increasing cGMP concentrations in uptake inhibitors, are associated with variable rates the corporal smooth muscle.11 Since premature of success when taken daily.5,8 In contrast some ejaculation, like psychogenic impotence, is a per- reports suggest that these drugs may be effective formance-anxiety problem in an otherwise normal when received as needed.4,9 Although behavioral male, it could be anticipated that oral sildena®l therapy requires partner cooperation, some reports would work in the treatment of premature ejaculation. Since the comparison of these different modalities when used as needed has not been evaluated, this study was undertaken to compare *Correspondence: IA Abdel-Hamid, Department of the ef®cacy and safety of as needed use of oral Andrology, Mansoura Faculty of Medicine, PO Box 35516, Mansoura, Egypt. clomipramine, sertraline, paroxetine, sildena®l and E-mail: [email protected] the Masters and Johnson pause-squeeze technique Received 3 August 2000; accepted 9 September 2000 in the treatment of primary premature ejaculation. Pharmacotherapy and the pause-squeeze technique in premature ejaculation IA Abdel-Hamid et al 42 Methods satisfaction questionnaire (patient version) designed by Althof et al13 for measuring the degree of sexual satisfaction among erectile dysfunction patients. From May 1999 to June 2000, 31 heterosexual men We found that the ®rst 9 items are applicable to complaining of primary premature ejaculation from premature ejaculation. Higher scores indicate great- the beginning of their sexual life were enrolled in er satisfaction. This questionnaire was translated this study. Premature ejaculation was de®ned as into Arabic by two independent translators. All intravaginal ejaculation latency time (IVELT) of less measurements were obtained before treatment, after than 2 minutes and the patient complained of little, each treatment and after each washout period. if any, control over their ejaculation. The patients Twenty healthy men who reported a sexual history were recruited from the outpatient clinic of the free of symptoms of premature ejaculation acted as a andrology and sexology unit, Mansoura University control group. The control group was subjected to Hospital, Mansoura, Egypt. All patients gave their measurement of anxiety score. After the completion verbal consent to participate in the study. Inclusion of the study, the unblinded code revealed that 7 criteria include persons married for at least 1 y and patients began with clomipramine, 6 with sertraline, willingness to attempt sexual intercourse at least 6 with paroxetine, 6 with sildena®l and 6 patients twice per week with a cooperative female partner. began with the pause-squeeze technique. Exclusion criteria include the following: (a) history of a psychiatric disorder; (b) current physical illness (eg, diabetes, liver disease and so forth); (c) previous Statistical analysis surgery or drug known to affect sexual function; (d) current substance abuse (alcohol or drug); (e) patients with secondary premature ejaculation The variables in this study were statistically pro- combined with erectile dysfunction. All patients cessed using SPSS program for windows, standard were asked not to use condoms or topical penile version, release 8.0. The data were subjected to applications. Kolmogorov-Smirnov one sample test, to test for The study utilized a prospective randomized normal distribution. This test showed that all the double blind crossover design. Treatment phases outcome variables were nonparametric. Nonpara- comprised ®ve 4-week consecutive treatment peri- metric statistical tests were used to assess differ- ods, each separated by a two-week washout period. ences in the measurements. Friedman's two-way Each patient was informed that he would be treated analysis of variance was used for comparison with 5 different modalities of therapies of identical between all the treatment periods. Wilcoxon signed action to ascertain which of the 5 was most useful. rank test was used for evaluation of measures The patients were randomly assigned to receive between baseline and after each treatment and also clomipramine hydrochloride 25 mg (Anafranil1, between each two treatment periods. The relation- Novartispharma, Cairo, Egypt), sertraline hydro- ship between parameters was quanti®ed by using chloride 50 mg (Lustral1, P®zer, Cairo, Egypt), the Spearman rank correlation coef®cient. Chi- paroxetine hydrochloride 20 mg (Seroxat1, Smith- square and Fisher exact tests were used for compar- KlineBeecham pharmaceuticals, Brentford, Eng- ison of the incidence of side effects among different land), sildena®l citrate 50 mg (Viagra1, P®zer, New treatments. Student's t-test and Chi-square test were York, USA) and to use the pause-squeeze technique used for comparison between the study group and according Masters and Johnson.2 The drugs were control group. A two-tailed P-value < 0.05 was administered as needed 3 to 5 hours before planned considered signi®cant. intercourse and not more than twice a week. The pause-squeeze technique was used during intercourse. Each patient was randomly assigned to Results receive any of the available treatments as the ®rst treatment and a sequence of treatment regimens. The assignment was unknown by the patient or the Table 1 shows the baseline characteristics of the investigator. Subjects were asked to complete a patient and control groups. Of 31 patients, 25 questionnaire, which we designed, that contained (80.6%) completed the 5 treatment periods. The 6 items such as intravaginal ejaculation latency time patients who dropped out of the study used between of the last 2 consecutive experiences of intercourse, 1 and 4 modalities (mean 3). Reasons for dropout frequency of intercourse and possible side effects. included lack of ef®cacy (clomipramine 2, sertraline Intravaginal ejaculation latency time was measured 2, paroxetine 2 and the pause-squeeze technique 2), by the patient using a watch. Anxiety measurement side effects (sildena®l 2) and lack of ef®cacy plus was assessed using an Arabic questionnaire (0 ± 30 side effects (clomipramine 1). Before treatment the scores) designed by Shaheen and Elrakhawy12 with anxiety score was signi®cantly higher among pa- higher scores indicating greater anxiety. We used tients in comparison with the control group (Table the ®rst 9-items (0 ± 30 scores) of the sexual 1). After 4-week treatments with clomipramine,

International Journal of Impotence Research Pharmacotherapy and the pause-squeeze technique in premature ejaculation IA Abdel-Hamid et al 43 Table 1 Baseline characteristics of patients and control group signi®cant positive correlation (r 0.666, P 0.01) between anxiety score and IVELT during treatment Patients Control Signi®cance n 31 n 20 test P with the pause-squeeze technique. Moreover, we found signi®cant negative correlation between Age (y) anxiety score and sexual satisfaction score dur- Range 27 ± 42 25 ± 46 ing treatment with the pause-squeeze technique Mean Æ s.d. 34.09 Æ 4.29 34.8 Æ 6.44 t 0.47 0.54 Median 34.0 33.5 (r 70.547, P 0.01), clomipramine (r 70.381, Duration of marriage (y) P < 0.05), sildena®l (r 70.573, P 0.01). Table 3 Range 1.5 ± 10.0 1 ± 10 t 0.39 0.39 displays overall incidence and types of the reported Mean Æ s.d. 3.6 Æ 2.1 3.4 Æ 2.1 side effects for each treatment. No adverse effects on Median 3.0 3.0 sexual function were noted. No statistically signi®- Education level High 18 (58.1%) 11 (55.0%) w2 0.047 0.83 cant differences were found with respect to side Middle 13 (41.9%) 9 (45%) effects of treatment between different drugs. Most of Anxiety score (Baseline) the side effects were mild to moderate in severity. Range 5 ± 25 1 ± 9 t 6.54 0.0001 Mean s.d. 12.7 Æ 5.8 3.7 Æ 2.7 Median 12 3.0 Discussion sertraline, paroxetine, sildena®l and the pause- squeeze technique, the median intravaginal ejacula- In the present study, treatment with clomipramine, tion latency time was signi®cantly increased from sertraline, paroxetine, sildena®l and pause-squeeze the pretreatment median of 1 minute to 4 minutes, technique as needed resulted in a statistically 3 minutes, 4 minutes, 15 minutes and 3 minutes signi®cant and clinically relevant delay of intra- respectively (Wilcoxon z 7 4.54, 74.63, 74.71, vaginal ejaculation latency time in patients with 74.63 and 74.55, respectively, all P < 0.0001). primary premature ejaculation. It is well established According to Friedman's test, treatment with silde- that the improvement of ejaculatory delay after as na®l caused a signi®cant increase in the median IVELT, median sexual satisfaction score and median IVELT during the washout period (Table 2). The most effective treatment in prolongation of IVELT Table 3 Side effects of different drugs was sildena®l in 28 patients (90.3%), followed by Sertraline Paroxetine Sildena®l Clomipramine paroxetine (80.6%), sertraline (71.2%), clomipramine (71%) and the pause-squeeze technique No. patients with 3 (10.3%) 5 (17.2%) 5 (17.9%) 7 (25%) side effects (%) (54.8%). Clomipramine, sertraline and paroxetine P-value* 0.27 0.69 0.75 were more or less equivalent to each other in terms No. of side effects of ejaculation latency time and sexual satisfaction Dry mouth 2 3 score (all P > 0.05). Paroxetine was found to be Anorexia 1 superior to the pause-squeeze technique in terms of Nausea 1 1 1 Headache 2 ejaculatory latency and sexual satisfaction score Flushing 2 (Wilcoxon z 72.05, P 0.04, z 72.24, P 0.025, Drowsiness 1 1 respectively). Sleepiness 2 Sexual satisfaction scores showed statistically Nasal congestion 1 signi®cant positive correlation with IVELT during Yawning 2 all treatment periods (all P 0.01). We noted *Compared to incidence of side effect with clomipramine.

Table 2 Comparison between different modalities

Baseline Clomipramine Sertraline Paroxetine Sildena®l Squeeze technique Friedman w2 dF P

Anxiety score Median 12 11 11 9 8 12 (Range) (5 ± 25) (4 ± 22) (5 ± 22) (5 ± 23) (4 ± 15) (5 ± 21) 55.15 5 0.0001 IVELT (min) Median 1 4 3 4 15 3 (Range) (0.5 ± 1.5) (1 ± 8) (1 ± 10) (2 ± 10) (5 ± 30) (1 ± 7) 92.53 5 0.0001 Sexual satisfaction score Median 11 10 12 30 6 (Range) (0 ± 25) (0 ± 31) (0 ± 29) (17 ± 34) (0 ± 22) 57.87 4 0.0001 IVELT during washout periods (min) Median 1 1 1 1.75 1 (Range) (0.5 ± 1.5) (0.5 ± 2) (0.5 ± 2) (0.5 ± 8) (0.5 ± 1.5) 32.52 5 0.0001

International Journal of Impotence Research Pharmacotherapy and the pause-squeeze technique in premature ejaculation IA Abdel-Hamid et al 44 needed treatment with clomipramine, sertraline and effectively. Other authors have found that treatment paroxetine is attributed to central inhibition of with sex therapy led to improvement for a minority serotonin reuptake,6 as it has been suggested that of patients.10 the serotoninergic system has inhibitory in¯uence Our data documented signi®cant positive correla- on ejaculation.5 This improvement associated with tion between ejaculation latency and sexual satisfac- antidepressant use cannot be ascribed to a decrease tion score during different treatment periods. Since in anxiety score, as this did not occur. Similar the higher sexual satisfaction could re¯ect an ®ndings, dosages and methods of administration increase in the control over ejaculation, this ®nding were reported.4,9,14,15 On the other hand, the is especially interesting, in view of the fact that excellent success associated with sildena®l use ejaculation latency and control tend to be related.23 could be attributed to three possible mechanisms. In view of the tendency of premature ejaculation The ®rst is reduction in performance anxiety, to relapse following discontinuation of the three because of signi®cant decrease in anxiety score antidepressants and the pause-squeeze technique, during treatment and this could explain the sig- because of the mean half-lives of clomipramine, ni®cant negative correlation between anxiety score sertraline and paroxetine are about 24, 26 and 21 and sexual satisfaction score. The second possible hours, respectively.24,25 In addition, behavioral explanation is that sildena®l may maintain erection techniques had not always been successful in the and increase the erection time, and ejaculation longterm.10 Although the half life of sildena®l is latency time was reported to be dependent on three to ®ve hours11 a signi®cant delay of ejaculation erection time.6 So, it is anticipated that sildena®l latency time during the washout period in 29% of could increase the ejaculation latency time. The last patients was surprising. This improvement could be mechanism is a possible central effect. Little due to reduction in performance anxiety induced by is known about the intensity of stimulus required initial successful sildena®l treatment. to induce ejaculation or the in¯uence of the cerebral Three limitations of the present study must be cortex on the ejaculation re¯ex, although the addressed. First, the sexual satisfaction instrument peripheral neural pathway involved in ejaculation used13 can not be applied before treatment to give is fairly well understood. Phosphodiesterase the baseline satisfaction because it is composed of 9 enzymes were shown to be present in the rat brain,17 items analysing all aspects of sexual satisfaction and nitric oxide, the intracellular messenger related to treatment. However, the questionnaire is of sildena®l, was reported to perform numerous valuable in comparative and controlled studies.13 physiological functions, one of which is neural Moreover, it must be remembered that men who communication in the brain.18 In addition, nitric participate in clinical trials are extremely motivated oxide-stimulated guanylyl cyclase activity within a and as such have a very low satisfaction level. For cellular environment is more complex than example, the range of sexual satisfaction scores previously assumed and associated with diversity during treatment with the 3 antidepressants and the of cellular responses.19 Hence it is possible that pause-squeeze technique started from zero. The sildena®l could have a central effect. Furthermore, it second limitation is that the patients gave a retro- has been suggested that nitric oxide activity in the spective assessment of the mean ejaculation latency medial preoptic area tonically inhibits ejaculation before treatment, after each treatment and after the by decreasing sympathetic tone.20 washout period. It is dif®cult for study participants Behavioral therapy, such as the Semans pause to recall events in the past. It would be better to maneuver1 which was modi®ed to the pause- record ejaculation latency time at each coitus. squeeze technique by Masters and Johnson,2 is However by asking the patients to report speci®cally considered the gold standard for treatment of on the last 2 consecutive experiences of intercourse, premature ejaculation.21 While these techniques the validity of the assessment of latency became are harmless and usually a painless treatment more reliable. The last limitation is the lack of a modality and have been fairly successful at rates of placebo control period. This is because our work 60 to 95%,22 they require partner cooperation and included two different modalities (drugs vs beha- usually the patients fail to maintain gains for the vioral) and it is unacceptable to include a placebo longterm.10 In our experience, the pause-squeeze control period of treatment. Furthermore, in cross- technique was associated with the lowest success over studies the patients may serve as their own rate (54.8%) compared with other modalities. In control.26 Moreover a placebo or untreated period addition, the technique was associated with lower may not be appropriate for diseases for which there sexual satisfaction score and lower ejaculation is proven effective treatment or a well-established latency in comparison with sildena®l and parox- standard treatment.27 etine, but comparable with clomipramine and It is known that selective serotonin reuptake sertraline. Contributing factors for this lower suc- inhibitors have a more favorable side effect pro®le cess may be that some patients are embarrassed to than clomipramine either when given on a daily involve their partners in the technique and others basis5,8 or on demand.4,9,15 This is because of ®nd that it is time consuming and does not work selective inhibition of serotonin reuptake and mini-

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International Journal of Impotence Research